A
variety of hepatic and biliary tract disorders may complicate the
clinical course of celiac disease. Some of these have been hypothesized
to share common genetic factors or have a common immunopathogenesis,
such as primary biliary cirrhosis, primary sclerosing cholangitis and
autoimmune forms of hepatitis or cholangitis. Other hepatic changes in
celiac disease may be associated with malnutrition resulting from
impaired nutrient absorption, including hepatic steatosis. In addition,
celiac disease may be associated with rare hepatic complications, such
as hepatic T-cell lymphoma. Finally, pancreatic exocrine function may be
impaired in celiac disease and represent a cause of treatment failure.

A
number of hepatobiliary and pancreatic disorders occur in celiac
disease, a genetically-based small intestinal disorder that resolves
with the complete restriction of dietary gluten[1]. Almost 3
decades ago, liver changes in celiac disease were first recognized by
Hagander et al[2]. Later, Dickey et al[3]
have confirmed these findings in a prospective evaluation of celiac
disease patients and extended observations to results of gluten-free
diet therapy. In some, these liver test changes are entirely reversible
following administration of a gluten-free diet, while in others,
clinically significant liver disease is not amenable to diet treatment
alone[3]. Now, almost a decade after this report, recognition
of celiac disease has been substantively improved, in part, a result of
more modern serological assays for screening[4], the
detection of tissue transglutaminase (tTG) as an autoantigen in celiac
disease[5] and the increasingly widespread serological use of
tTG ELISA to screen for celiac disease[6]. As a result of
improved recognition of celiac disease, even more precise estimates of
the overall disease burden related to hepatobiliary tract and pancreatic
disorders will emerge.

In
patients with unexplained elevations of liver enzymes, several studies
using serological screening methods have estimated that almost 10% will
prove to have celiac disease[7,8]. For example, Volta et
al[7] examined endomysial and gliadin antibodies in 55
patients with elevations of liver chemistry tests in the absence of a
known cause. Five patients had positive serological studies and small
intestinal biopsies showed changes of celiac disease that responded to a
gluten-free diet. Liver biopsies done in some patients showed a
nonspecific inflammatory process and liver chemistry tests normalized
with a gluten-free diet. Bardella et al[8] screened
140 patients with chronically elevated transaminase values for gliadin
and endomysial antibodies; of these, 13 were sero-positive. After 1 year
on a gluten-free diet, 12 patients had normalization of liver enzyme
tests.

In
celiac disease, persistently abnormal liver chemistry tests may reflect
the presence of a clinically occult hepatobiliary tract disorder with a
possibly common immunopathogenesis. Specific examples of immune-mediated
disorders include primary biliary cirrhosis, primary (lymphocytic,
autoimmune) sclerosing cholangitis or autoimmune hepatitis.
Alternatively, in some, a common genetically-based disorder, including
altered control of small intestinal iron absorption resulting in a
concomitant iron overload disorder, may be present, such as
hemochromatosis. In addition, chronic changes in liver chemistry tests
may reflect a direct effect of the celiac disease. For example, impaired
absorption and resultant malnutrition may lead to deposition of fat in
the liver, related, in part, to reduced fat mobilization from
hepatocytes. Indeed, massive hepatic steatosis has occasionally been
reported in celiac disease. Finally, but very rarely, patients may
develop a specific complication of celiac disease that involves the
liver, such as a T-cell form of lymphoma.

HEPATOBILIARY TRACT DISEASES

Primary biliary cirrhosis

In
1978, Logan et al[12] described the first cases of
primary biliary cirrhosis with celiac disease. Later, numerous
additional cases have been reported[13-16]. In both
disorders, other conditions having an immunological basis have been
described, including diabetes and thyroiditis[16-19]. In
addition, co-existence of primary biliary cirrhosis and celiac disease
has not only been reported in Europe and the Americas, but also in
migrants from South Asia[20] and the Coast Salish, an
aboriginal population inhabiting the west coast of Canada thought to be
of Asian descent[16]. To date, however, a definitive genetic
predisposition or specific immunological alteration has not been clearly
identified. Loss of weight, malabsorption, osteopenic bone disease,
steatorrhea and elevated alkaline phosphatase activities are common
features of both diseases, so that early in their coexistence, celiac
disease or primary biliary cirrhosis may not be easily appreciated. In
patients reported with both disorders, regardless of geographical origin
or race, restriction of dietary gluten may have improved the diarrhea,
but abnormal liver chemistry tests were usually not significantly
altered with a gluten-free diet.

Some
more recent studies have explored serological testing in primary biliary
cirrhosis or celiac disease. Kingham and Parker[21] used a
patient registry in the United Kingdom and defined the prevalence of
primary biliary cirrhosis in 143 celiac patients as 3%, while the
prevalence of celiac disease in 67 primary biliary cirrhosis patients
was 6%. As a result, screening with antimitochrondrial antibodies in
celiac disease was recommended, while in primary biliary cirrhosis,
serological screening with gliadin antibodies or small intestinal biopsy
was suggested. Dickey et al[22] found similar findings
of 7% (4/57) primary biliary cirrhosis patients based on initial
evaluation using endomysial antibodies (11% positive), followed by later
duodenal biopsy confirmation. Despite 12 to 24 mo on gluten-free diets,
however, improvement in liver chemistry tests was not detected even
though endomysial antibodies disappeared. Using Danish and Swedish
registry data based on over 8 000 patients with celiac disease, Sorensen
et al[23] also suggested an increased risk of primary
biliary cirrhosis. Using stored sera from 378 Canadian patients with
primary biliary cirrhosis, Gillett et al[24] found
that screening for IgA antibodies to endomysium and primary biliary
cirrhosis were both positive in 10 (2.6%) patients and 5 patients had
small intestinal biopsies confirming celiac disease. Intertestingly,
however, another 44 primary biliary cirrhosis patients had raised IgA
tissue transglutaminase antibodies but were negative for IgA endomysium
antibody. In 255 patients with autoimmune cholestatic liver disorders,
including 173 with primary biliary cirrhosis, Volta et al[25]
found 9 with celiac disease (including 7 in those with primary biliary
cirrhosis, 4%). In some recent studies, however, the importance of
biopsy confirmation in patients with primary biliary cirrhosis has been
demonstrated in sero-positive patients as false-positive IgA or IgG tTG
antibodies may occur in primary biliary cirrhosis[26,27].

In a
recent study using a general practice longitudinal database from the
United Kingdom[28], an overall 3-fold risk of primary biliary
cirrhosis was demonstrated in 4 732 patients diagnosed with celiac
disease as compared with 23 620 age- and sex-matched controls.

Primary sclerosing cholangitis

Primary sclerosing cholangitis was first found to be associated with
celiac disease in 1988 in 3 patients with diarrhea and steatorrhea[29].
Two also had concomitant “ulcerative colitis” (one with “inactive”
quiescent disease and one with “mild” or “minimal change” colonic
disease), a disorder known to be associated with primary sclerosing
cholangitis. Although hepatobiliary tract changes were defined by
cholangiography and liver biopsy, these did not respond to a gluten-free
diet. Later, other cases were reported[10,25,30]. In one, the
predominant lymphocytic nature of the portal inflammatory process was
emphasized with increased intra-epithelial lymphocytes in biliary ductal
epithelium[30], an observation also noted in gastric and
colonic epithelium of celiac patients[31,33]. To date,
despite some case report data[33], it has been difficult to
show good evidence for a response of the hepatobiliary tract disease to
a gluten-free diet. This may, in part, reflect sampling difficulties
associated with liver biopsy as well as the response or lack of response
of relatively non-specific liver chemistry test markers of cholestasis
(e.g., serum alkaline phosphatase). Indeed, the origin of alkaline
phosphatase activities measured in serum include the hepatobiliary tract
and other tissues that may be substantially altered in celiac disease
(i.e., bone and the intestine); conceivably all might be improved with a
gluten-free diet.

Autoimmune hepatitis and cholangitis

This
has been evaluated in only a limited numbers of case reports and survey
studies. Unfortunately, many appeared before hepatitis C testing[13,35].
Jacobsen et al[10] performed liver biopsies in 37 of
171 celiac patients and found changes of “chronic active hepatitis” in 5
(2.3%) patients. Using antibodies to endomysium and gliadin, Volta et
al[36] surveyed 157 patients with type 1 autoimmune
hepatitis and 24 with type 2 autoimmune hepatitis for celiac disease.
They found that 8 of these 181 (4%) patients were positive for
endomysial antibodies, including 6 (4%) with type 1 disease and 2 (8%)
with type 2 disease. Five of the 8 patients had a duodenal biopsy, most
being asymptomatic, and all showed changes of subtotal villous atrophy,
consistent with untreated celiac disease. The effects of steroid with or
without azothioprine treatment on the underlying small intestinal
histological changes were considered and also may have masked intestinal
symptoms. Unfortunately, in this study, the effects of gluten-free diet
administration on the hepatic and intestinal changes were not reported.
Recently, Villalta et al[37] evaluated 47 consecutive
patients with autoimmune hepatitis, including 39 with type 1 disease and
8 with type 2 disease. Anti-IgA tissue transglutaminase and endomysial
antibodies were positive in 3 (6.4%) patients and small intestinal
biopsies confirmed the presence of the celiac disease histological
changes[37].

Finally, celiac disease and other types of autoimmune liver and biliary
tract disease may coexist. A case report of autoimmune cholangitis[38],
a cholestatic liver disorder with biochemical evidence of cholestasis,
histological evidence of inflammatory bile duct damage and an absence of
anti-mitochondrial antibodies, was has been described in a patient with
celiac disease. Interestingly, this patient’s small intestinal biopsies
were reported to be normal without a gluten-free diet while being
treated with steroids and azathioprine. In an another case, Sedlack
et al[39] reported an improvement in hepatic
biochemistries without use of immunosuppressive agents.

HEMOCHROMATOSIS OR IRON OVERLOAD LIVER DISEASE

Celiac
disease has been associated with hemochromatosis, which is not
surprising, since both are relatively common disorders based on a common
Celtic ancestry, so any association could be coincidental[40-42].
Iron absorption largely occurs in the proximal duodenum, the site most
often histologically altered in celiac disease. Indeed, “isolated” iron
deficiency with anemia may be the initial clinical manifestation of
clinically occult celiac disease. In contrast, in iron overload liver
disease, inappropriate iron absorption from the proximal small intestine
occurs as body iron stores are markedly increased. In one of these early
case reports, treatment of celiac disease and improvement in the
pathological small intestinal changes led to worsening liver chemisty
test values and recognition of occult iron overload liver disease
(C282Y-negative), presumably related to improved intestinal uptake of
dietary iron[41]. Another similar case of C282Y-positive
hemochromatosis presented with diarrhea, positive anti-gliadin and
endomysial antibodies. Subsequent small bowel biopsies showed villous
atrophy[42]. Interestingly, in this latter case, phlebotomy
therapy had to be terminated early because of an unexpectedly rapid fall
in the serum ferritin measurement. A genetically-based linkage was also
suggested since both diseases are associated with the HLA-region on
chromosome 6. Later investigations have sought to resolve this possible
relationship. Butterworth et al[43] observed that HFE (hemochromatosis
susceptibility gene) locus mutations are common in celiac disease
patients from the United Kingdom and may be important in protecting the
celiac from iron deficiency, while others suggested that the
significance of these observations may be controversial[44].
More recent studies in an Italian population with untreated celiac
disease found that HFE mutations failed to protect against the
development of iron deficiency[45]. Interestingly, in a
recent case study of a patient with homozygous C282Y and celiac disease[46],
reduced expression of the divalent metal transporter 1 (DMT1) was
observed, but not ferroportin 1 (FP1) or transferrin receptor 1 (TfR1).

OTHER LIVER DISORDERS IN CELIAC DISEASE

Hepatic steatosis

Common
causes of hepatic steatosis include alcohol-induced steatosis, diabetes
mellitus, NASH syndromes and some forms of drug therapy, including
corticosteroids. In some countries, dietary protein deficiency and
kwashiorkor are important causes. Intestinal malabsorption is often
associated with hepatic steatosis in patients with a prior jejunoileal
bypass procedure for morbid obesity[47,48] and, sometimes, in
those with inflammatory bowel disease, particularly after extensive
intestinal resections[49]. Because celiac disease is now
frequently recognized in a clinically occult form before manifestations
of marked nutrient depletion are detected, hepatic steatosis is probably
less common than in other intestinal diseases.

Several cases of fatty infiltration of the liver, often massive, have
been described in adults with celiac disease[50-53].
Presumably, lesser degrees of hepatic fat deposition may occur. Most
often if massive steatosis is evident, elevated transaminase and
alkaline phosphatase activities have been documented along with
alterations in coagulation. However, in most, clinical and biochemical
changes attributed to the hepatic steatosis were improved with a
gluten-free diet. In a patient with massive hepatic steatosis[52],
a gluten-free diet for about 1 year also resulted in histological
improvement in the fatty changes detected in the liver.

The
mechanisms involved in fat deposition in the liver are not defined.
Interestingly, after jejunoileal bypass, reduced serum levels of some
essential and nonessential amino acids may be observed[47,48].
In addition, changes in serum amino acids have been recorded in patients
with starvation-associated kwashiorkor[54,55]. Based on these
nutritional disorders, it has been suggested that malabsorption in
celiac disease might lead to chronic deficiency of a lipotropic factor
(e.g., choline), with an associated pyridoxine deficiency, hepatic
steatosis might occur[52]. Further studies are needed to
define the precise pathogenetic mechanism or mechanisms for fatty liver
in celiac disease.

Gallstone disease

Several studies have focused on gallbladder function in celiac patients.
In some studies, slow emptying of the gallbladder has been documented[56,57],
along with impaired contraction response to fat[56]. Studies
of enteric endocrine cells showed significant quantitative changes in
celiac patients, including complete absence of mucosal secretin cells[59].
In addition, studies with test meals have suggested impaired secretion
of cholecystokinin in patients with celiac disease[59] or,
possibly, impaired gallbladder responsiveness to cholecystokinin[56].

In
spite of these physiological alterations, there does not appear to be a
significant predisposition to gallstones in celiac disease. Only 9 of
350 patients had a cholecystectomy for gallstone disease[60].
However, in a survey of elderly celiacs initially diagnosed after the
age of 60 years, 6 of 30 (20%) had gallstone disease[61].

Hepatic vein obstruction

Although mesenteric vascular ischemia[62] and vasculitis[63-66]
have been described in celiac disease, there are also reports of a
unusual Budd-Chiari-like syndrome among celiac children from North
Africa, particularly Tunisian and Algeria[67,68]. Hepatic
vein obstruction has also been documented in 3 adults[69].
Deficiencies in protein C and antithrombin III are detected, and
malabsorption of vitamin K in celiac disease has been proposed to cause
transient protein C or protein S deficiencies. Further studies are
needed to identify possible factors, either dietary or environmental
agents, that may be important. More recently, a celiac patient with a
Budd-Chiari syndrome associated with membranous obstruction of the
inferior vena cava treated successfully with percutaneous balloon
angioplasty has been reported[70].

Hepatic malignancies

While
hepatocellular cancer has been reported in 1 patient, cirrhosis was also
present[71]. Occasionally, the liver may be involved with
lymphoma, the most frequently detected malignant disorder in celiac
disease patients[72]. In some patients with celiac disease,
lymphomatous deposits have been detected in the liver, presumably as
metastatic lesions[71]. For example, lymphoma in the liver is
apparently secondary to jejunal lymphoma, complicating celiac disease[71].
In general, involvement of the liver in celiac disease patients with
lymphoma is limited and overshadowed by the clinical course of the
intestinal disease. However, a fulminant cholestatic syndrome has been
described in a celiac disease patient, resulting in hepatic failure[73].
Later investigations have shown widespread hepatic involvement with an
unusual lymphoid neoplasm classified as a hepatosplenic lymphoma, a rare
type of peripheral T-cell lymphoma with rearrangement of the gamma-delta
T-cell receptor[74,75].

Liver failure

In
patients with severe liver failure from a variety of causes in celiac
disease, dietary treatment reverses hepatic dysfunction, even in
patients with consideration for possible liver transplantation[76].

PANCREATIC DISEASE

While
celiac disease is associated with insulin-dependent diabetes[77],
pancreatic exocrine insufficiency and celiac disease have only
occasionally been recorded[78-84]. Pancreatic calcification
is most often associated with chronic or persisting pancreatic
inflammation which is usually due to excessive consumption of alcoholic
beverages. Atophy, fibrosis and altered pancreatic function have been
observed in experimental animals treated with diets deficient in
protein, in adults with protein-energy malnutrition, in children with
kwashiorkor and in some early autopsy studies of patients with celiac
disease. In addition, pancreatic calcification has been reported with
chronic protein malnutrition in the Indian subcontinent and in some
African countries. Finally, a patient with celiac disease and
pancreatitis with calcification has been described[83].

Although the frequency of pancreatic disease in celiac patients is not
known, impaired pancreatic function occurs and may be a cause of
persistently impaired nutrient assimilation and malnutrition. It has
been estimated that over 20% of children with celiac disease have
defective exocrine pancreatic function[85]. This may be
related to several factors. Impaired secretion and/or release of
pancreatic stimulating hormones from the diseased proximal small
intestine may be important[60]. Immunohistochemical studies
have demonstrated alterations in enteric endocrine cells, and in
biopsies from patients with untreated celiac disease, an absence of
secretin cells has been reported[59]. Studies with test meals
in celiac patients have suggested impaired secretion of
cholecystokinin-pancreozymin resulting in reduced pancreatic exocrine
cell stimulation[81]. In addition, a deficiency of amino
acids may result from impaired small intestinal amino acid uptake,
leading to a reduction in precursors for pancreatic enzyme synthesis[55,80].
Also, protein malnutrition may lead to structural changes in the
pancreas, including atrophy of acinar cells and pancreatic fibrosis[55],
resulting in impaired pancreatic exocrine function. In a more recent
study[86], pancreatic enzyme measurements were reduced with
mucosal atrophy and could be inversely correlated with the degree of
intestinal damage.

3Dickey
W,
McMillan SA, Collins JS, Watson RG, McLoughlin JC, Love AH. Liver
abnormalities associated with celiac sprue. How common are they, what is
their significance, and what do we do about them? J Clin
Gastroenterol 1995; 20: 290-292PubMed